The present invention generally relates to methods and apparatus for rapidly screening an array of diverse materials which have been created at known locations on a single substrate surface, and in particular to the combinatorial synthesis and characterization of libraries of diverse materials using IR imaging and spectroscopy techniques.
The discovery of new materials with novel chemical and physical properties often leads to the development of new and useful technologies. Currently, there is a tremendous amount of activity in the discovery and optimization of materials, such as superconductors, zeolites, magnetic materials, phosphors, catalysts, thermoelectric materials, high and low dielectric materials and the like. Unfortunately, even though the chemistry of extended solids has been extensively explored, few general principles have emerged that allow one to predict with certainty the composition, structure and reaction pathways for the synthesis of such solid state compounds.
The preparation of new materials with novel chemical and physical properties is at best happenstance with our current level of understanding. Consequently, the discovery of new materials depends largely on the ability to synthesize and analyze new compounds. Given approximately 100 elements in the periodic table that can be used to make compositions consisting of two or more elements, an incredibly large number of possible new compounds remains largely unexplored. As such, there exists a need in the art for a more efficient, economical and systematic approach for the synthesis of novel materials and for the screening of such materials for useful properties.
One of the processes whereby nature produces molecules having novel functions involves the generation of large collections (libraries) of molecules and the systematic screening of those collections for molecules having a desired property. An example of such a process is the humoral immune system which in a matter of weeks sorts through some 1012 antibody molecules to find one which specifically binds a foreign pathogen (Nisonoff et al., The Antibody Molecule (Academic Press, New York, 1975)). This notion of generating and screening large libraries of molecules has recently been applied to the drug discovery process.
Applying this logic, methods have been developed for the synthesis and screening of large libraries (up to 1014 molecules) of peptides, oligonucleotides and other small molecules. Geysen et al., for example, have developed a method wherein peptide syntheses are carried out in parallel on several rods or pins (J. Immun. Meth. 102:259-274 (1987), incorporated herein by reference for all purposes). Generally, the Geysen et al. method involves functionalizing the termini of polymeric rods and sequentially immersing the termini in solutions of individual amino acids. In addition to the Geysen et al. method, techniques have recently been introduced for synthesizing large arrays of different peptides and other polymers on solid surfaces. Pirrung et al. have developed a technique for generating arrays of peptides and other molecules using, for example, light-directed, spatially-addressable synthesis techniques (U.S. Pat. No. 5,143,854 and PCT Publication No. WO 90/15070, incorporated herein by reference for all purposes). In addition, Fodor et al. have developed a method of gathering fluorescence intensity data, various photosensitive protecting groups, masking techniques, and automated techniques for performing light-directed, spatially-addressable synthesis techniques (Fodor et al., PCT Publication No. WO 92/10092, the teachings of which are incorporated herein by reference for all purposes).
Using these various methods, arrays containing thousands or millions of different elements can be formed (U.S. patent application Ser. No. 08/805,727, filed Dec. 6, 1991, the complete disclosure of which is incorporated herein by reference for all purposes). As a result of their relationship to semiconductor fabrication techniques, these methods have come to be referred to as xe2x80x9cVery Large Scale Immobilized Polymer Synthesis,xe2x80x9d or xe2x80x9cVLSIPS(trademark)xe2x80x9d technology. Such techniques have met with substantial success in screening various ligands such as peptides and oligonucleotides to determine their relative binding affinity to a receptor such as an antibody.
The solid phase synthesis techniques currently being used to prepare such libraries involve the sequential coupling of building blocks to form the compounds of interest. For example, in the Pirrung et al. method polypeptide arrays are synthesized on a substrate by attaching photoremovable groups to the surface of the substrate, exposing selected regions of the substrate to light to activate those regions, attaching an amino acid monomer with a photoremovable group to the activated region, and repeating the steps of activation and attachment until polypeptides of the desired length and sequence are synthesized. These solid phase synthesis techniques cannot readily be used to prepare many inorganic and organic compounds.
In PCT WO 96/11878, the complete disclosure of which is incorporated herein by reference, methods and apparatus are disclosed for preparing a substrate with an array of diverse materials deposited in predefined regions. Some of the methods of deposition disclosed in PCT WO 96/11878 include sputtering, ablation, evaporation, and liquid dispensing systems. Using the disclosed methodology, many classes of materials can be generated combinatorially including inorganics, intermetallics, metal alloys, and ceramics.
In general, combinatorial chemistry refers to the approach of creating vast numbers of compounds by reacting a set of starting chemicals in all possible combinations. Since its introduction into the pharmaceutical industry in the late 80""s, it has dramatically sped up the drug discovery process and is now becoming a standard practice in the industry (Chem. Eng. News Feb. 12, 1996). More recently, combinatorial techniques have been successfully applied to the synthesis of inorganic materials (G. Briceno et al., SCIENCE 270, 273-275, 1995 and X. D. Xiang et al., SCIENCE 268, 1738-1740, 1995). By use of various surface deposition techniques, masking strategies, and processing conditions, it is now possible to generate hundreds to thousands of materials of distinct compositions per square inch. These materials include high Tc superconductors, magnetoresistors, and phosphors. Discovery of heterogeneous catalysts will no doubt be accelerated by the introduction of such combinatorial approaches.
A major difficulty with these processes is the lack of fast and reliable testing methods for rapid screening and optimization of the materials. Recently, a parallel screening method based on reaction heat formation has been reported (F. C. Moates et al., Ind. Eng. Chem. Res. 35, 4801-4803, 1996). For oxidation of hydrogen over a metallic surface, it is possible to obtain IR radiation images of an array of catalysts. The hot spots in the image correspond to active catalysts and can be resolved by an infrared camera.
Screening large arrays of materials in combinatorial libraries creates a number of challenges for existing analytical techniques. For example, traditionally, a heterogeneous catalyst is characterized by the use of a micro-reactor that contains a few grams of porous-supported catalysts. Unfortunately, the traditional method cannot be used to screen a catalyst library generated with combinatorial methods. First, a heterogeneous catalyst library synthesized by a combinatorial chemistry method may contain from a few hundred to many thousands of catalysts. It is impractical to synthesize a few grams of each catalyst in a combinatorial format. Second, the response time of micro-reactors is typically on the order of a few minutes. The time it takes to reach equilibrium conditions is even longer. It is difficult to achieve high-throughput screening with such long response times.
Another challenge with screening catalyst arrays is the low level of components that may be present in the reactions. The consequence of low level catalytic material is a low conversion rate. For example, oxidation of ethylene to ethylene oxide can be carried out over a silver-based catalyst (S. Rebsdat et al., U.S. Pat. Nos. 4,471,071 and 4,808,738). For a surface-supported catalyst with an area of 1 mm by 1 mm and the same activity as the industrial catalyst, only about 10 parts per billion (ppb) of ethylene are converted into the desired ethylene oxide when the contact time is one second.
Detection of such low component levels in the presence of several atmospheres of reaction mixture is a challenge to analytical methods. Many analytical techniques, including optical methods such as four-wave mixing spectroscopy and cavity ring-down absorption spectroscopy as well as conventional methods such as GC/MS, are excluded because of poor sensitivities, non-universal detectability, and/or slow response. Therefore an apparatus and methodology for screening a substrate having an array of materials that differ slightly in chemical composition concentration, stoichiometry, and/or thickness is desirable.
The present invention provides methods and apparatus for the rapid characterization and analysis of an array of materials using infrared imaging and spectroscopy techniques. Typically, each of the individual materials on the array will be screened or interrogated for the one or several material characteristics. Once screened, the individual materials may be ranked or otherwise compared relative to each other with respect to the material characteristic under investigation. Materials that can be compared using the methods and apparatus of the present invention include, for example liquids, dissolved organic or inorganic molecules, covalent network solids, ionic solids and molecular solids. In particular, the present invention is directed to characterization systems utilizing thermal imaging and infrared spectroscopic imaging.
According to one aspect of the present invention, infrared imaging techniques are used to identify the active compounds within an array of compounds by monitoring temperature change in the vicinity of the compound. Temperature change results from a reaction, either exothermic or endothermic in nature, and may be localized to specific compounds within the library as well as the region of the substrate adjacent to the compounds in question. This same technique can also be used to quantify the stability of each new material within an array of compounds by observing the temperature change as a function of time. By measuring the decay of activity through the change in temperature over time for each site, the lifetime of catalysts, for example, can be quantified.
According to another aspect of the invention, identification and characterization of the condensed solid or liquid phase products is achieved, wherein library elements are characterized by their specific infrared absorption or reflectance. Such materials may be the product of reactions, for example, in the gas phase polymerization of ethylene to condensed phase polyethylene or in the hydrolysis of liquid dimethyldichlorosilane to elastomeric polydimethylsiloxane. In one embodiment specific molecular vibrations are evaluated by measuring the IR absorption. Typically, the radiation from a monochromatic infrared source is passed through the library and the intensity of the transmitted beam is measured as a function of time during the progression of a reaction. In an alternate embodiment, the library is irradiated with polychromatic infrared radiation and an infrared bandpass filter is used to confine the detection to specific wavelength regions of the infrared spectrum.
In another aspect of the invention, heat transport properties are measured using the rate of heat dissipation in a library by observing the transient change in temperature of the library elements with infrared imaging. Preferably, a pulsed infrared source illuminates the back surface of the library while the front surface of the library is monitored. Thus a measure of the thermal conductivity of each of the elements can be easily obtained.
According to a further aspect of the invention, identification and characterization of material properties is achieved using a two-dimensional infrared imaging system. The imaging system simultaneously monitors each element of the library, wherein each individual library element""s temperature as well as its difference relative to the surrounding elements reflects the activity and heat of reaction of the specific library site.
A further understanding of the nature and advantages of the inventions herein may be realized by reference to the remaining portions of the specification and the attached drawings.